Increased vascular permeability and uncontrolled accumulation of activated neutrophils in the interstitium is the hall mark of acute lung injury. The vascular endothelium, which lines all blood vessels, is the first entry point for neutrophils transmigration to underlying tissue. In general, naïve endothelium is “unactivated or anti-inflammatory” as it dynamically allows neutrophils to survey the underlying tissue for host-defense. How then endothelium acquire “immune activated state” without encountering infectious injury leading to neutrophils influx and inflammatory tissue injury remains elusive. We have discovered that ERG, a transcription factor belonging to ETS related gene (ERG), instructs endothelial anti-inflammatory niche and thereby prevents neutrophil activation and vascular injury. We found that conditional deletion of ERG in adult endothelium of the mice (iEC-ERG-/-mice) spontaneously increased vascular permeability and accumulation of activated neutrophils in the air space. Moreover, iEC-ERG-/- mice developed inflammation as reflected by increased NFκB activity and pro-inflammatory cytokines/chemokines accumulation including IL-8. Neutrophil egress is influenced by the local production of chemokine ligands like IL-8. Moreover, deubiquitinase A20 is the critical negative regulator of NFκB signalling and thereby inflammation. We show that loss of ERG in endothelium led to reduced A20 expression in mouse and human lung endothelial cells (EC). We therefore assess if rescuing A20 levels or inhibiting IL8 will restore lung inflammatory injury in EC-ERG null mice. Rescuing A20 expression in human lung EC suppressed the level of cytokines to the level as seen in controls. To investigate the role of IL-8 in activating neutrophil influx we used Reparixin, an allosteric inhibitor of IL-8 receptor. Reparixin was administered to iEC-ERG-/-mice and FACS analysis was performed. Results showed markedly reduced inflammation and neutrophil influx in the Reparixin treated ERG null mice. Collectively, our observations show that ERG depletion causes low A20 levels leading to uncontrolled NFκB activation and IL-8 chemokine secretions triggering neutrophil mobilization. We conclude that ERG expression is required in endothelium for maintaining anti-inflammatory ‘immune niche’ to prevent neutrophil influx and inflammatory injury.